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BACKGROUND: Erythropoietic-stimulating agents such as erythropoietin have been used as part of patient blood management programs to reduce or even avoid the use of allogeneic blood transfusions. We review the literature to evaluate the effect of preoperative erythropoietin use on the risk of exposure to perioperative allogeneic blood transfusions.

CONCLUSIONS: Preoperative erythropoietin is associated with a significant reduction in perioperative allogeneic blood transfusions. This finding is also confirmed among the subset of patients undergoing cardiac and orthopedic surgery. Furthermore, our study demonstrates no significant increase in risk of thromboembolic complications with preoperative erythropoietin administration.

Blood transfusion is the most common procedure performed during inpatient hospitalizations in the United States as noted by the Health Care Cost and Utilization Project. While medically indicated transfusions are lifesaving, unnecessary perioperative blood transfusion has been associated with higher incidence of hospital-acquired infections and thrombotic complications,1,2 and large-volume transfusions (≥10 red blood cell units) are associated with a dose-dependent increase in rates of infection, thrombotic events, and overall mortality.3 Recently, there has been a nationwide effort to decrease transfusion overuse in the perioperative setting. A number of high-quality prospective trials have focused on optimizing transfusion practices in the setting of cardiac surgery, where providers have long implemented concerted efforts to reduce or avoid blood transfusions. These efforts have included the identification of ideal hemoglobin transfusion triggers as well as the designation of surgical blood conservation strategies such as use of minimally invasive approaches, cell-saving technologies, blood-conserving cardiopulmonary bypass practices, and the ubiquitous use of antifibrinolytics.4

Patient blood management programs have been shown to substantially reduce blood utilization and blood acquisition costs.5 One often overlooked component of a successful blood management program involves consideration for optimization of the preoperative hemoglobin concentration and mitigation of preprocedural anemia. Erythropoietic-stimulating agents have been used previously in the surgical setting as a method to potentially reduce or avoid the use of allogeneic blood transfusions. Unfortunately, studies have yielded generally mixed results and previous systematic reviews are either dated, failed to provide comprehensive details regarding the impact of individual surgical procedures (ie, orthopedic and cardiac surgery), or have not addressed potential confounders such as the use of concomitant blood conservation strategies.6–8 Since the institution of a Food and Drug Administration black box warning regarding the potential risk of thromboembolic events associated with erythropoietin administration, the practice has largely fallen out of favor in the United States aside from isolated clinical circumstance such as in the management of Jehovah’s Witnesses or patients with bleeding dyscrasias. In an era where providers are increasingly challenged to provide high-value perioperative care, our group sought to review the available literature, with relevant updates over the past decade, to evaluate the effect of preoperative erythropoietin administration on the likelihood of exposure to allogeneic blood transfusions as well as the incidence of perioperative thromboembolic events.

METHODS

Search Strategy

This study used the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. We searched Medline, Embase, and CINAHL for all available studies from inception onward, with updates to January 2018 (Supplemental Digital Content 1, Search Strategy, http://links.lww.com/AA/C690). In addition, individual citations were reviewed from included studies. Inclusion criteria included the following: (1) population: studies involving adult (>18 years of age) human patients undergoing surgery; (2) intervention: erythropoietin administered in the preoperative period at least before incision; (3) predefined outcomes: incidence of allogeneic red blood cell transfusion during inpatient hospitalization; and (4) design: randomized controlled trials published in English, full-text versions. No minimum sample size or dosing regimen was required for inclusion.

Data Extraction

Two authors (B.C.C., J.S.) screened the titles and abstracts of initial search results, extracted data, and assessed for risk of bias independently. Disagreements were resolved by a third reviewer (M.C.G.). Demographic and clinical data, including transfusion end points, were extracted from qualified studies and subsequently analyzed. Risk of bias was assessed using the Cochrane Collaboration tool, which considers 7 domains including adequacy of sequence generation, allocation concealment, blinding of participants, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other potential sources of bias.9

Primary Outcomes

The primary end point of the analysis is reported incidence of allogeneic red blood cell transfusion during inpatient hospitalization. Predetermined subgroup analysis was performed when appropriate by pooling and analyzing data based on (1) surgical subtype, with particular emphasis applied to cardiac and elective orthopedic surgery, and (2) the use of alternative blood conservation strategies (ie, autologous blood donation, acute normovolemic hemodilution, and intraoperative autologous blood salvage). Further post hoc subgroup analysis was performed that included studies with common dosing regimens for preoperative erythropoietin.

Secondary Outcomes

The secondary end points included phase-specific number of allogeneic red blood cell transfusions received (ie, intraoperative, postoperative, composite) as well as intraoperative estimated blood loss. We qualitatively evaluated the effects of preoperative erythropoietin administration on hospital length of stay and perioperative hemoglobin levels. We also abstracted data regarding relevant side effects such as thromboembolic events, previously undiagnosed hypertension, and potential drug reactions. Studies that did not evaluate these side effects were left out of the analysis.

For dichotomous data, risk ratio was used to describe the size of the treatment effect, and for continuous data, standard mean difference was used. When multiple preoperative erythropoietin dosing regimens were assessed in a single study, arms were combined into a single treatment result rather than dividing arms into separate groups to avoid unit-of-analysis error. A random-effects model was used for all analyses. Heterogeneity was measured and expressed as I2, which describes the percentage of total variation across studies that is due to heterogeneity rather than chance. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity. We performed leave-one-out sensitivity analysis to determine the robustness of the pooled estimate by sequentially removing each study and reanalyzing the remaining data sets. Publication bias was calculated using the Egger test. Funnel plots were constructed to represent any tendency for publishing in favor of the positive effect. Significant publication bias was considered when there was asymmetry in the funnel plot (meaning that smaller studies tend to show larger risk ratios) and a statistically significant bias coefficient according to the Egger test. Sensitivity analysis was performed excluding high risk of bias studies (where greater than one-third of pooled trials resulted in high risk of a bias for a particular risk of bias domain), and any potential influence on outcome was subsequently reported in the results. Level of significance for all analyses was set at .05. All statistical analyses were performed with Review Manager (RevMan) 5.3 (The Cochrane Collaboration, London, UK, 2014) and confirmed with Stata version 13.0 (Stata, College Station, TX).

RESULTS

Literature Identification

The initial search resulted in 3216 abstracts (549 from PubMed, 1738 from Embase, 653 from Web of Science, and 276 from Cochrane Library). After removing 919 duplicate studies, 2297 potentially relevant articles were screened on basis of the abstract. After removing 2172 abstracts that did not meet inclusion criteria, the remaining 122 full-text articles were thoroughly reviewed. An additional 90 articles were excluded on the following basis: no data on the outcomes of interest, lack of patient randomization, pediatric patient population, or studies that included autologous blood donations. Thirty-two studies10–42 (Figure 1; n = 4750 patients) were included in the final analysis that compared preoperative erythropoietin administration (n = 2482) to placebo controls (n = 2268).

Study Characteristics

Table 1 summarizes the study characteristics including patient numbers, patient demographics, erythropoietin route and dose, surgery type, and all other noted blood conservation strategies. The dose and route of erythropoietin varied significantly between the individual studies. Cardiac surgery was the most prevalent with 10 studies, followed by elective orthopedic (7), gastrointestinal (7), gynecological (2), nonelective orthopedic (2), urologic (1), and transplant (1) procedures thereafter. One study evaluated all “elective procedures.” Supplemental Digital Content 1, Figure 1, http://links.lww.com/AA/C690, illustrates the Cochrane Risk of Bias reporting for all included studies. All studies were randomized, but selection bias was unclear (method for randomization was not explicitly described) for 2 of 32 trials (6.25%). In addition, only 8 of 32 (25%) trials described their method for intervention concealment. The potential for detecting bias was also noted in 9 of 32 (28.1%) trials.

Perioperative Hemoglobin Levels

A majority of the studies evaluated did not provide quantitative hemoglobin levels but rather visually demonstrated changes in hemoglobin levels through the use of a graph or figure. Therefore, qualitative assessment was performed among trials (n = 25) to evaluate the impact of preoperative erythropoietin administration on perioperative hemoglobin levels. Among trials that reported on the end point, preoperative erythropoietin was associated with a significantly higher preoperative (15 of 21 trials) and postoperative (21 of 23 trials) hemoglobin level compared to placebo counterparts.

Hospital Length of Stay

Qualitative assessment was also performed among trials (n = 12) to evaluate the impact of preoperative erythropoietin administration on hospital length of stay. Among trials that reported on the end point, preoperative erythropoietin was not associated with a qualitative difference compared to placebo counterparts. Three of the 12 studies demonstrated a shorter hospital length of stay with preoperative erythropoietin compared to placebo counterparts, while 3 of the 12 studies demonstrated a longer length of stay with preoperative erythropoietin compared to placebo counterparts. The remaining 6 studies demonstrated no difference in hospital length of stay between the 2 groups.

Side Effects and Complications

Preoperative erythropoietin administration was not associated with increased incidence of thromboembolic events (n = 28; risk ratio, 1.02; 95% CI, 0.78–1.33; P = .68; P for heterogeneity = .64; I2 = 0%) compared to placebo (Figure 3). Four trials noted a single instance each of myocardial infarction within the preoperative erythropoietin group, while 1 trial noted a single instance of myocardial infarction in the placebo group. The rates of previously undiagnosed hypertension were not different between the 2 groups, while there was a slight increase in the number of minor adverse drug reactions in the preoperative erythropoietin group. These reactions included skin reactions, chills, and nausea. No other relevant side effects were identified in the studies.

DISCUSSION

The results of our meta-analysis suggest that preoperative erythropoietin administration in the setting of iron supplementation is associated with a significant reduction in perioperative allogeneic blood transfusions. This finding was confirmed among both cardiac and elective orthopedic procedures. Further, preoperative erythropoietin use is associated with a significant reduction in the number of intraoperative, postoperative, and whole-hospital red blood cell transfusions in isolation. Qualitative review suggests that preoperative erythropoietin administration results in higher hemoglobin levels at all perioperative time points compared to placebo. Finally, preoperative erythropoietin did not result in a significant increase in risk of either thromboembolic or other significant side effects. Our review builds on previous literature reporting the benefits of erythropoietin administration, which has largely been focused on the medical (nonprocedural) setting and subsequent risk of exposure to allogeneic blood transfusion.6–8

Given the noted risks and associated costs with allogeneic blood transfusions, it is important to consider all relevant blood conservation strategies to minimize exposure. Methods include intraoperative blood salvage, acute normovolemic hemodilution, restrictive transfusion triggers, administration of hemostatic agents including antifibrinolytics, and the use of erythropoietin. Erythropoietin has been previously studied, and its use is associated with a decreased risk of exposure to allogeneic blood transfusions, particularly in the medical population.43 However, given the concern for potential increased risk of thromboembolic events, the Food and Drug Administration issued a black box warning in 2007 for erythropoietin.44 Since that time, its use for elective surgery has generally fallen from favor. Three previous systematic reviews have been performed to evaluate the effectiveness of erythropoietin among surgical patients and concluded—similar to our study—that its use was associated with a reduction in allogeneic blood transfusion.6–8 Although potentially informative, all 3 studies included patients who also received preoperative autologous blood transfusions, a practice that is not commonly performed today. In an effort to remove this important confounder, we sought to specifically isolate preoperative erythropoietin as the primary documented intervention, excluding other methods (eg, autologous blood salvage, preoperative autologous blood collection, or acute normovolemic hemodilution). While Laupacis and Fergusson7 performed a systematic review focused on orthopedic and cardiac surgeries, their study included only 400 cardiac surgery participants and represents data before 1998. There are likely considerable advances in surgical approach, perioperative management, and general transfusion practices since that time (eg, lower hemoglobin thresholds for transfusion). While their findings complement ours—namely that preoperative erythropoietin was associated with a reduction in allogeneic blood transfusions—our study expands considerably on theirs both in number of included patients and investigation of relevant medication side effects.7 Alghamdi et al6 performed a review that focused specifically on cardiac surgical patients. Again, our study expands considerably on this patient population (700 vs 1500+ patients) and we include data on a host of other surgical procedure subtypes. Alsaleh et al8 performed a review that focused specifically on elective orthopedic surgery patients. While they also found that preoperative erythropoietin was associated with a reduction in allogeneic blood transfusions, our study verifies this finding and further expands on the effects of preoperative erythropoietin in other surgical specialties.

Perioperative allogeneic blood transfusion remains a widely debated and well-studied topic, particularly in cardiac surgery, with multiple randomized controlled trials evaluating the appropriateness of various hemoglobin transfusion triggers. The recent Transfusion Requirements in Cardiac Surgery III trial concluded that a transfusion trigger of hemoglobin <7.5 g/dL in cardiac surgical patients was noninferior to a more liberal transfusion trigger.45 Despite attempts to reduce transfusion, cardiac surgery–related blood transfusions reached a high in the United States in 2010, with 34% of patients receiving blood products.46 Our review specifically evaluated cardiac surgery studies and found that preoperative erythropoietin administration is associated with nearly a 50% reduction in risk of exposure to allogeneic blood transfusions, an effect that spanned the perioperative continuum. Our analysis also addressed the use of preoperative erythropoietin among elective orthopedic procedures and found similar efficacy.

While it is best practice to use evidence-based transfusion triggers, it may be even more efficacious to optimize patients ahead of their surgical encounter. Comprehensive perioperative programs such as Enhanced Recovery After Surgery have identified appropriate preoperative, intraoperative, and postoperative process measures that lessen the impact of surgery and hasten surgical recovery.47,48 These programs, initiated in Europe and later adopted in the United States, are growing in popularity. While attention has been provided to preoperative patient education, preemptive analgesia, nutrition, and even prehabilitation, guidelines have failed to provide formal recommendations regarding a strategy to optimize hemoglobin levels and/or comprehensively manage perioperative transfusion.47,48 By utilizing preoperative erythropoietin along with iron supplementation, it is likely patients can improve their baseline hemoglobin levels and thus reduce the likelihood of crossing established transfusion thresholds (ie, hemoglobin triggers or targets). And as our results suggest, this practice would decrease the likelihood of allogeneic blood transfusions.

Perhaps just as importantly, the beneficial impact of preoperative erythropoietin on rates of perioperative transfusion is complemented by the fact that its administration was not associated with a higher incidence of thromboembolic events. Although the majority of the included studies were not designed to evaluate for thromboembolic events (ie, these were included principally as secondary end points detecting only clinically evident events), it is nonetheless encouraging to note that there was no significant difference between groups. The Food and Drug Administration warning associated with erythropoietin use specifically references increased risk of thromboembolic events among patients who are not receiving chemical thromboprophylaxis, a practice that is now almost universally adopted during the surgical period. Further, given a significant cultural shift in the past decade in the management of surgical patients associated with the adoption of Enhanced Recovery After Surgery programs, patients are routinely ambulating early after surgery, thereby reducing the nidus for thrombosis.47,48 It is possible that the issued warning should be reevaluated in light of these new findings.

There are several important limitations to our review. First, our results are associated with a high degree of heterogeneity. This can likely be attributed to a variety of dosing strategies, including absolute dose, medication timing, and route of drug administration. While the dosing regimen of 300 mg/kg was the only regimen to be associated with a significant decrease in allogenic blood transfusions among further subgroup analysis, there are a number of other factors that may affect this result including variability in dose timing and type of surgery. Given this variability, we cannot provide official recommendations regarding the optimal dosing regimen to minimize risk of transfusion. In fact, controlled studies are needed to identify a standardized dosing regimen of erythropoietin to optimize hemoglobin increases and reduce the risk of allogeneic blood transfusions. It is possible that the type of procedure contributed to heterogeneity as well. This review includes studies that span over 2 decades in an effort to pool all relevant data. In that time, there have been advancements in both blood management and surgical technique that are likely to affect the results of this review. With this in mind, we attempted to correct for advancements in blood management by excluding studies with additional blood conservation techniques. Another limitation included a potential to be inadequately powered to detect a difference in thromboembolic rates between the preoperative erythropoietin group and the placebo groups. Our reported overall rate of thromboembolic events was 4.13% while published rates of thromboembolic events after surgery for all patients range from 0.96% to 2%.49,50 The increased rates associated with our study are likely secondary to the fact that a majority of our patients were undergoing high-risk surgery. Despite this higher incidence, we did not detect a difference between groups, which is encouraging and unlikely to be the result of an underpowered study. We cannot, however, exclude the possibility of detection bias given that thromboembolic events were included as secondary outcomes in most included trials.

The results of this meta-analysis of randomized controlled trials suggest that preoperative erythropoietin administration is associated with a significant reduction in the risk of exposure to allogeneic blood transfusions in the perioperative period compared to placebo, and that its use was not associated with an increased risk of thromboembolic events. Based on the results of this study, preoperative erythropoietin is not only a viable agent for reducing perioperative transfusion requirements, but it may also be time to reconsider its routine use as a tool for preoperative optimization, particularly for procedures associated with high incidence of blood product administration such as cardiac and orthopedic surgeries.